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||Genetic Causality of Alcohol Intake and Alcohol Use Disorder on Cancer Risk
Genetic Causality of Alcohol Intake and Alcohol Use Disorder on Cancer Risk
Alcohol use and alcohol use disorder (AUD) are among the leading causes of death and disability worldwide.
Ethanol, i.e. beverage alcohol, is mainly oxidized by alcohol dehydrogenases (several ADH genes) to
acetaldehyde, which is then detoxified to acetate by aldehyde dehydrogenases (mainly ALDH2). Acetaldehyde
and alcoholic beverages are classified as carcinogenic to humans by the International Agency for Research on
Cancer. Cumulative epidemiological evidence has shown that alcohol consumption is associated with the
development of cancers including upper aerodigestive tract, breast, liver and colorectal cancer; 5.5% of all
cancers are attributable to alcohol, totaling 770,000 cases annually. A better understanding of the molecular
basis by which alcohol increases cancer risk could lead to improved treatment and preventative strategies.
Genome-wide association studies (GWASs) have identified risk genes for alcohol-related traits and cancers,
and some genes show pleiotropic effects on both. However, the genetic relationship between alcohol and
cancers remains largely unclear. Recently, large GWASs have been conducted on alcohol-related traits and
cancers, provided opportunities to answer the above question. The proposed study will take advantage of large
scale genetic data in multiple populations to discover genetic risk variants playing roles in both alcohol-related
traits (alcohol use and AUD) and alcohol-associated cancers, study the genetic correlations among them, and
investigate the genetic causality between alcohol traits and cancers using Mendelian Randomization (MR).
Additionally, by integrating summary data regarding large-scale gene expression, eQTL, mQTL, metabolomic
QTL and proteomic QTLs into 2-step MR, we aim to identify genes whose expression levels are associated
with alcohol-associated cancer variation, identify regulatory and epigenetic markers that mediate the
relationship between alcohol and cancers, and identify the relevant pathway mechanisms that involve
acetaldehyde and, potentially, other metabolites. This study will help us to understand better the genetic
mechanisms that underlie the relationship between alcohol traits and alcohol-associated cancers, with the
potential to improve disease prevention and treatment strategies.